Blocking a key inflammatory pathway improves liver structure and vascular function in cirrhosis, study finds

Researchers from Miguel Hernández University of Elche (UMH) in Spain have identified an effective strategy to reduce structural liver damage and improve hepatic vascular function in cirrhosis. The study, published in Biomedicine & Pharmacotherapy, also reveals a key inflammatory mechanism that contributes to liver injury and could be targeted to develop new treatments for a disease responsible for more than one million deaths worldwide each year.

The work was led by Rubén Francés Guarinos, researcher in the Department of Clinical Medicine at UMH, in collaboration with the Institute for Health Biotechnology Research, Development and Innovation of Elche (IDiBE UMH), the Hepatic Vascular Biology Group at Hospital Clínic of Barcelona, and the Spanish Biomedical Research Network in Hepatic and Digestive Diseases (CIBERehd).

“Our main objective was to understand the role of platelet-activating factor (PAF) and its receptor (PAF-R) in liver cirrhosis, a disease characterized by progressive liver damage accompanied by intense chronic inflammation,” explains Francés. The study also evaluated whether blocking this inflammatory pathway could be an effective strategy to improve liver function in cirrhosis.

Liver cirrhosis is a severe and progressive condition in which healthy liver tissue is gradually replaced by scar tissue, leading to loss of structure and function. Globally, it affects more than one million people and accounts for approximately 2.4% of all deaths, underscoring its major public health impact. “Beyond mortality, cirrhosis involves a high burden of complications—including infections, bleeding, cognitive impairment, and loss of autonomy—that profoundly affect patients’ quality of life,” the researcher adds.

Despite this impact, current therapeutic options remain limited and often focus on managing complications rather than correcting the biological mechanisms that drive liver damage. This highlights the need for studies that deepen understanding of disease mechanisms and open new, more effective intervention pathways.

To address this, the researchers compared different experimental treatments in both healthy and cirrhotic liver tissue. Specifically, they administered a PAF antagonist, BN-52021, which blocks the PAF-R receptor, as well as an inhibitor known as Aza, which acts by modifying the epigenetic regulation of the receptor. The study included advanced analyses such as DNA methylation profiling to understand why PAF-R expression is abnormally increased in cirrhosis.

The work was conducted using liver samples from patients with cirrhosis to confirm the relevance of the mechanism in humans, as well as in a mouse model of experimental liver injury. The analyses focused particularly on hepatic immune cells known as Kupffer cells, which play a central role in inflammatory responses in the liver.

The main finding of the study is that an epigenetic mechanism drives the increased expression of PAF-R in these inflammatory cells. In cirrhosis, demethylation of the promoter region of the PAF-R gene removes a chemical mark that normally restrains its expression. As a result, the gene becomes overactivated, the number of PAF-R receptors increases, and inflammation and liver damage are amplified.

The results also show that treatment with the PAF antagonist BN-52021 effectively reduces structural liver damage and improves hepatic vascular function in cirrhotic mice. This treatment also helps rebalance immune and inflammatory responses within the liver.

“Taken together, these findings suggest that drugs capable of blocking PAF action, such as BN-52021, could represent a new therapeutic line for liver cirrhosis,” concludes UMH researcher Enrique Ángel Gomis, first author of the study. The results also open the door to therapies aimed at correcting the epigenetic mechanisms regulating PAF-R, with the goal of controlling inflammation and liver damage at their molecular origin.